Kinins are natural vasoactive peptides liberated in the body from high molecular weight precursors (kininogens) by the action of selective proteases known as kininogenases.
There is evidence for the involvement of kinins in the following pathological states:
(a) Conditions associated with vasodilatation and hypotension, e.g. septic, anaphylactic and hypovolaemic shock; carcinoid syndrome and dumping syndrome PA1 (b) Conditions involving inflammation, e.g. acute arthritis, pancreatitis, local thermal injury, crush injury and brain oedema PA1 (c) Conditions involving bronchoconstriction, especially for example the initial, acute allergic reaction in asthma PA1 (d) Allergic inflammation, particularly allergic rhinitis and conjunctivitis, together generally known as hay fever, and the bronchial inflammation and consequent occlusion found in the non-acute but serious and even fatal inflammatory phase of asthma. PA1 (a) They increase capillary permeability which leads to exudate formation and oedema PA1 (b) They are potent vasodilators in arterioles and therefore reduce blood pressure and increase blood flow PA1 (c) They induce pain PA1 (d) They contract bronchial smooth muscle PA1 (e) They activate phospholipase A.sub.2 and thus stimulate the biosynthesis of prostaglandins (PG's) which mediate some of their actions. PA1 (a) Tissue kallikrein (TK, also called glandular kallikrein GT or urinary kallikrein UK) which is found in the pancreas, brain, salivary and sweat glands, intestines, kidney and urine. It has MW=30,000 and acts preferentially on low molecular weight kininogen (LMWK) to release the kinin kallidin (KD). Tissue kallikrein has no potent and fast acting endogenous inhibitor present in plasma. Recently it has been established that at least three homologous genes code for TK's. The hPK gene is expressed in the tissues mentioned above. Additionally, the PSA gene encodes a prostate specific TK and the hGK-1 gene expresses a TK in neutrophils. PA1 (b) Plasma kallikrein (PK) occurs in plasma as an inactive zymogen which is activated by Factor XIIa, and is part of the intrinsic coagulation cascade. It has MW =100,000 and its preferred substrate is high molecular weight kininogen (HMWK) from which it releases bradykinin (BK). Plasma kallikrein is rapidly and effectively inhibited in plasma, by endogenous inhibitors known as cl-inactivator and .alpha..sub.2 -macroglobulin. PA1 (c) Mast cell tryptase (MT) has been found in large amounts in the pulmonary mast cells of asthmatics. MT has been shown to release bradykinin from both LMWK and HMWK and may therefore be of aetiological significance in asthma (as indeed TK appears to be). PA1 (a) Low molecular weight kininogen (LMWK) with molecular weight in the range 50,000-70,000 depending on species of origin and degree of glycosylation. PA1 (b) High molecular weight kininogen (HMWK) with molecular weight in the range 88,000-114,000 which, in addition to serving as an alternative precursor of kinins and a cysteine proteinase inhibitor, also plays an obligatory role with plasma kallikrein in the initiation of the intrinisic coagulation cascade. PA1 (1) Allergic inflammation (e.g. asthma, rhino-conjunctivitis [hay fever], rhinorrhoea, urticaria), excess lung mucus, ascites build-up. PA1 (2) Inflammation (e.g. arthritis, pancreatitis, gastritis, inflammatory bowel disease, thermal injury, crush injury, conjunctivitis), periodontal disease, chronic prostate inflammation, chronic recurrent parotitis, inflammatory skin disorders (e.g. psoriasis, eczema), hepatic cirrhosis, spinal cord trauma and SIRS (systemic inflammatory response syndrome). PA1 (3) Smooth muscle spasm (e.g. asthma, angina), RDS (respiratory distress syndrome). PA1 (4) Hypotension (e.g. shock due to haemorrhage, septicaemia or anaphylaxis, carcinoid syndrome, dumping syndrome) PA1 (5) Oedema (e.g. burns, brain trauma, angioneurotic oedema whether or not as a result of treatment with inhibitors of angiotensin converting enzyme) PA1 (6) Pain and irritation (e.g. burns, wounds, cuts, rashes, stings, insect bites), migraine. PA1 (7) Male contraceptive agents by virtue of inhibition of prostate kallikrein. PA1 (8) Prevention of excessive blood loss during surgical procedures. PA1 (9) Growth factor regulation: TK is implicated in processing of precursors of various growth factors e.g. EGF, NGF. PA1 R.sup.1, R.sup.2, R.sup.3, R.sup.4, are --H, alkyl (C1 to C6), --OH, alkoxy, halide, --SH, or --S--alkyl (C1 to C6), or one or both of R.sup.1 R.sup.2, R.sup.3 R.sup.4, constitute a carbonyl group or a cycloalkyl (C3 to C6) group; D is --NR.sup.11 --where R.sup.11 .dbd.H, lower alkyl C1 to C6 or OH; or SO.sub.2, CO, CH.sub.2, O or S; or .dbd.CH--(when the amide bond between B and C is replaced by --CH.dbd.CH--); PA1 E is --CR.sup.5 R.sup.6 --(defined as R.sup.1 R.sup.2, R.sup.3 R.sup.4 above); --NR.sup.11 --(R.sup.11 as above); O; or S; PA1 ii) A and B, one of which may be absent, are amino acyl or amino acyl analogue residues the same or different and in particular: PA1 a) a residue of an amino or imino acid or analogue of L- or preferably D- configuration and preferably selected from Aib; Aic; Ala; Aha(2-aminohexanoic acid, also known as norleucine); Apa; Arg; Atc; Aze; Bta; Cdi; Cha; Cin; Cit; Cpg(cyclopentylglycine); .alpha.-Dhn; .beta.-Dhn; Dpn; Glu; 4-Gph; 3-Gph; Har; Hch; Hci; His; Hph; Hyp; Ile; Leu; Lys; Nip; .alpha.-Nal; B-Nal; 2-Pal, 3-Pal; 4-Pal; Phe; 4-CF.sub.3 -Phe; 4-Cl-Phe; 4-CN-Phe; 4-F-Phe; 3-F-Phe; 2-Me-Phe; 4-NO.sub.2 -Phe; 4-NH.sub.2 -Phe; 2,4-Cl.sub.2 -Phe; 3,4-Cl.sub.2 -Phe or other substituted Phe; Phg; Pic; Pro; .beta.-Pro; 3-Ph-Pro; .alpha.-homo-Pro; Pse; Pse(OR) where R=Cl to C10 alkyl; Pyr; Ser; Ser (O.sup.n Bu); Tal; Tic; .alpha.-Tna; Trp; Tyr; Tyr(Et); Val; optionally with an N-terminal group which may in particular be selected from --HCO, lower alkyl-(C1 to C6)--acyl or aromatic acyl; lower alkyl (C1 to C6)-sulphonyl; alkyl (C1 to C10); HO.sub.2 C(CH.sub.2).sub.n -, where n=1 to 3, or esters or amides thereof; amino-acyl; alkyloxycarbonyl; aryloxycarbonyl; R-alkylacyl where alkyl is C1 to C10 and end-group R is selected from guanidino, amidino, benzamidino, guanidinophenyl and amidinophenyl; aryl sulphonyl; or in general a Boc, Z, Fmoc or other protecting group; PA1 b) an N,N-diaikyl--(C1 to C20) substituted, or N,N-[HO.sub.2 C(CH.sub.2).sub.n -].sub.2 - (n=1 to 3) substituted amino acid preferably of D- configuration and preferably as above; PA1 c) a group as follows (B=absent) ##STR3## where n=1 to 5; R.sup.7 =a lipophilic group such as aryl, heteroaryl or alkyl (C1 to C20) and preferably Nap, substituted Nap, cyclooctyl, or decahydronaphthyl; and R.sup.8 =R.sup.7 preferably phenyl (including substituted phenyl) or heteroaryl, and in particular phenylalkyl acyl-, D- or L- aryl- or heteroaryl- alaninyl, or aryl- or heteroaryl- aminoalkyl generally (where `alkyl` is C1 to C6 and aryl may be substituted); PA1 iii) further: PA1 the amide function --CONH--between A and B, or B and C (when D .dbd.NH), or both may be replaced by a mimetic including --CH.dbd.CH--; --CF.dbd.CH--; --CH.sub.2 NR.sup.12 --where R.sup.12 .dbd.H, alkyl, OH; --COCH.sub.2 --; --CH(OH)CH.sub.2 --; --CH.sub.2 O--; --CH.sub.2 S--; --CH.sub.2 SO.sub.x --where x=1, 2; --NH CO--; --CH.sub.2 CH.sub.2 --; or heterocyclic rings as under definition of C (when D, E, F may also be encompassed). Such mimetics are well known in the scientific literature especially in the area of peptidomimetic research; PA1 "alkyl" unless otherwise specified encompasses straight-chain, branched and cyclo. PA1 The invention also relates to a pharmaceutically active compound comprising a residue of the above-formula but lacking the hydrogen attached to D, or having in the place of that hydrogen a carbonyl group, or having in place of the amide group that is formed by D and such a carbonyl group an amide-group structural mimetic.
The kinins (bradykinin, kallidin and Met-Lys-bradykinin) are potent mediators of inflammation. Their main actions are as follows:
In regard to prostaglandins, it may be noted that certain actions of kinins, particularly pain and vascular permeability above, are potentiated by PG's, although PG's themselves do not cause pain nor do they induce vascular permeability at the concentrations found in inflamed tissue. PG's therefore act as either mediators or potentiators of kinins.
In spite of the above knowledge of kinins and their actions, relatively little attention has been paid to reduction of their action. In asthma treatment for example clinical attention is primarily directed to the acute bronchoconstrictive reaction, for which there are effective drugs. Deaths continue to occur from the gradually developing bronchial occlusion. At present there are no selective inhibitors of kinin release in clinical use, and their potential use in allergic inflammation appears to have been unpublished prior to our PCT application WO 9204371 of Mar. 19, 1992.